Activation-induced cell death (AICD) of over-stimulated T cells has been proposed to be an important mechanism in homeostasis and the prevention of autoimmunity. Repeated stimulation of T cells through T cell antigen receptor (TCR) induces co-expression of Fas and Fas ligand (FasL) on the surface of T cells, and the Fas-FasL interaction leads to the "suicide" or "fratricide" of T cells. Proteoglycan (PG)-induced arthritis (PGIA) is a novel autoimmune murine model induced by systemic immunization of mice with cartilage PG. In this model, an aberrant proliferation of peripheral CD4+ T cells in vitro in response to TCR stimulation was associated with low levels of AICD and a high ratio of interferon (IFN)-gamma to interleukin (IL)-4 in arthritic mice. The defective AICD and hyper-proliferation of CD4+ T cells in mice with PGIA may be ascribed to failure of inducing degradation of cellular Fas-associated death domain (FADD)-like IL-1beta-converting enzyme (FLICE)-inhibitory protein (c-FLIP). The incidence and severity of PGIA is augmented in IL-4-deficient (IL-4-/-) mice in comparison to wild-type (Wt) BALB/c mice, whereas administration of IL-4 to BALB/c mice greatly reduces disease. Moreover, PG-primed IL-4-/- CD4 + T cells fail to undergo apoptosis. Based upon these observations, we hypothesize that loss of IL-4 leads to a failure of inducing c-FLIP degradation which in turn results in defective AICD and hyperproliferation of autoreactive Th1-type cells in the periphery, thus leading to the development of PGIA. To confirm our hypothesis, we propose three specific aims: (1) We will define whether and how loss of IL-4 results in accumulation of CD4+ T cells in IL-4-/- mice with PGIA in vivo; (2) We will investigate whether c-FLIP regulates hyper-proliferation and defective AICD of arthritogenic CD4+ T cells in IL-4-/- mice with PGIA; and (3) We will determine whether IL-4 regulates the susceptibility of autoreactive T cells to AICD by adjusting cell cycle progression, and investigate whether IL-4 regulates cell cycle progression through controlling c-FLIP expression. The information generated by the proposed studies will enhance our understanding of the biological function of IL-4 and will shed light on the development of novel therapeutic approaches to autoimmune arthritis.